Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients

Abstract

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch) cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms. Hence, in a previous study, we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls. Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

The relationship between disaccharidase deficiencies and irritable bowel syndrome in childre - A literature review

“…This is vital as, despite available evidence, many pediatric gastroenterologists do not test for these deficiencies 5 . Less invasive studies, such as genetic testing and breath testing 44,45,48,49 , may encourage physicians to consider testing for disaccharidase deficiency as part of the workup for pediatric IBS when indicated.…”

“…Heterozygous carriers of the CSID mutation had an almost 2-fold increased risk of IBS (p = 0.074; odds ratio = 1.84) 43 . In a genotype study of 2207 IBS patients, Garcia-Etxebarria et al (2018) found that when compared with matched reference population from exome aggregation consortium, most SI rare pathogenic variants were identified in IBS patients and further analysis showed these variants increased the risk of IBS 45 . Table 2 outlines the studies referred to in this review that found a link between disaccharidase deficiencies and IBS.…”

“…Their testing found 100% sensitivity 53 . Studies by 44,45 . Development of cost-effective, less invasive methods is crucial as physicians are more likely to include these in the workup of their patients diagnosed with IBS in whom they suspect a disaccharidase deficiency.…”

Management of Irritable Bowel Syndrome: Physician‐Dietitian Collaboration

“…43,44 When symptoms of bloating, gas, and diarrhea are present and not fully managed by medical and nutrition therapies for IBS, sucrase-isomaltase deficiency (SID) should be considered. 45,46 Genetic mutations in the SI gene affects sucrose and disaccharide digestion in congenital SID or SID when found in adulthood and may cause symptoms similar to IBS. 46 Diagnosis of SID may be made through symptom development with sucrose ingestion, a carbon 13 ( 13 C-sucrose) breath test, or endoscopic biopsy.…”

“…45,46 Genetic mutations in the SI gene affects sucrose and disaccharide digestion in congenital SID or SID when found in adulthood and may cause symptoms similar to IBS. 46 Diagnosis of SID may be made through symptom development with sucrose ingestion, a carbon 13 ( 13 C-sucrose) breath test, or endoscopic biopsy. In this case, the breath test has been shown to be accurate and does not cause symptoms as would occur with actual sucrose ingestion.…”